Regulation of secretion of Alzheimer amyloid precursor protein by the mitogen-activated protein kinase cascade.
Activation of protein kinase C (PKC) regulates the processing of Alzheimer amyloid precursor protein (APP) into its soluble form (sAPP) and amyloid beta-peptide (A beta). However, little is known about the intermediate steps between PKC activation and modulation of APP metabolism. Using a specific inhibitor of mitogen-activated protein (MAP) kinase kinase activation (PD 98059), as well as a dominant negative mutant of MAP kinase kinase, we show in various cell lines that stimulation of PKC by phorbol ester rapidly induces sAPP secretion through a mechanism involving activation of the MAP kinase cascade. In PC12-M1 cells, activation of MAP kinase by nerve growth factor was associated with stimulation of sAPP release. Conversely, M1 muscarinic receptor stimulation, which is known to act in part through a PKC-independent pathway, increased sAPP secretion mainly through a MAP kinase-independent pathway. A beta secretion and its regulation by PKC were not affected by PD 98059, supporting the concept of distinct secretory pathways for A beta and sAPP formation.
Desdouits-Magnen
J
J
Laboratory of Molecular and Cellular Neuroscience and Zachary and Elizabeth M. Fisher Center for Research on Alzheimer's Disease, Rockefeller University, New York, New York 10021, USA.
Desdouits
F
F
Takeda
S
S
Syu
L J
LJ
Saltiel
A R
AR
Buxbaum
J D
JD
Czernik
A J
AJ
Nairn
A C
AC
Greengard
P
P
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis*; D000818:Animals; D016466:CHO Cells; D019556:COS Cells; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D006224:Cricetinae; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008301:Maleimides / Q000494:pharmacology; D020929:Mitogen-Activated Protein Kinase Kinases; D018721:Muscarinic Agonists / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000378:metabolism*; D051381:Rats; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000502:physiology
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007211:Indoles; D008301:Maleimides; D018721:Muscarinic Agonists; D009414:Nerve Growth Factors; D047428:Protein Kinase Inhibitors; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D015240:Phorbol 12,13-Dibutyrate; D002217:Carbachol; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C070515:bisindolylmaleimide I; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one